Dravet syndrome is caused by loss-of-function mutations in the SCN1A gene, which codes for the alpha subunit of the NaV1.1 sodium channel. However, there are other sodium channels, and it is known that gain-of-function mutations in SCN8A, the gene that codes for the alpha subunit of the NaV1.6 sodium channel, can lead to severe epileptic conditions. This suggests that NaV1.1 and NaV1.6 exist in a balance that maintains proper nerve conduction. It raises the possibility that Dravet syndrome might be treated not just by by restoring or enhancing NaV1.1 function, but alternatively by reducing NaV1.6 activity.
To test this hypothesis, the authors tested both NaV1.1 activating drugs and NaV1.6 inhibiting drugs. They utilized a zebrafish model of Dravet Syndrome (see summary this month of paper by Ghannad-Rezaie et al. for a discussion of how zebrafish genes can be engineered to cause a condition that closely mimics Dravet syndrome). They found that a NaV1.1 activating compound (“AA43279”) and two NaV1.6 inhibitors (“MV1369” and “MV1312”) all significantly reduced seizure activity in these zebrafish. This supports the concept that inhibition of NaV1.6 could be just as efficient as activation of NaV1.1 for treating Dravet syndrome.